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Diabetes mellites (DM) is correlated with increased susceptibility to and disease progression of tuberculosis (TB), and strongly impairs effective global TB control measures. To better control the TB-DM co-epidemic, unravelling the bidirectional interactivity between DM-associated molecular processes and immune responses to  Mycobacterium tuberculosis  ( Mtb)  is urgently required. Since poly (ADP-ribose) polymerase (PARP) activation has been associated with DM and with  Mtb  infection in mouse models, we have investigated whether PARP inhibition by pharmacological compounds can interfere with host protection against  Mtb  in human macrophage subsets, the predominant target cell of  Mtb . Pharmacological inhibition of PARP decreased intracellular  Mtb  and MDR- Mtb  levels in human macrophages, identifying PARP as a potential target for host-directed therapy against  Mtb . PARP inhibition was associated with modified chemokine secretion and upregulation of cell surface activation markers by human macrophages. Targeting LDH, a secondary target of the PARP inhibitor rucaparib, resulted in decreased intracellular  Mtb , suggesting a metabolic role in rucaparib-induced control of  Mtb . We conclude that pharmacological inhibition of PARP is a potential novel strategy in developing innovative host-directed therapies against intracellular bacterial infections.

Pharmacological Poly (ADP-Ribose) Polymerase Inhibitors Decrease Mycobacterium tuberculosis Survival in Human Macrophages